Obesity in the United States and other industrialized nations has increased rapidly over the last thirty years and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity- linked disorders, such as diabetes, atherosclerosis and certain types of cancer. Despite an increase in white adipose tissue (WAT) mass being the defining characteristic of obesity, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with different risks of developing diabetes and other obesity-associated pathologies. However, the cellular and molecular mechanisms that control WAT mass in distinct depots are not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. The excessive accumulation of WAT in obesity results from an increase of both adipocyte size (hypertrophy) and number (hyperplasia). Since mature adipocytes are post-mitotic, they are generated from the proliferation and differentiation of adipoctye precursor cells. We have recently identified adipocyte progenitors and preadipocytes in vivo, allowing us to determine the cellular and molecular mechanisms that control adipocyte progenitor contribution to WAT mass in vivo. We hypothesize that by identifying the initiating signals that regulate the tissue-intrinsic control of WAT mass in specific depots we will be able to determine the mechanisms that integrate WAT with other tissues in the body to regulate metabolism and energy balance. To address this hypothesis, we will study two different models of WAT mass accumulation: 1) the excessive accumulation of WAT mass during the onset of high fat diet-induced obesity and 2) the establishment of WAT mass during development in normal mice. In each of these models we will define the timing of the activation of adipocyte precursor proliferation and differentiation into mature adipocytes, and determine the turnover rates of mature adipocytes. We will also determine the molecular mechanisms that regulate WAT mass in development and in diet-induced obesity, potentially leading to the identification of obesity-specific mechanisms of WAT mass regulation. Identifying molecular mechanisms that regulate WAT mass will lead to the development of therapeutics for the treatment of obesity and obesity-associated pathologies, such as diabetes and heart disease.

Public Health Relevance

Obesity, which is defined as an excessive accumulation of fat mass, is currently one of the leading public health challenges. Obesity is a legitimate public health concern for two reasons: 1) several other diseases are associated with obesity, including diabetes, cardiovascular disease and cancer, and 2) the rates of obesity have increased rapidly over the last forty years with almost one third of the adult population in the U.S. being classified as obese today. The goal of this proposal is to identify signals within fat that regulate fat mass, which may lead to the development of novel therapies for the treatment of obesity and obesity-related pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090489-03
Application #
8409832
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$379,286
Indirect Cost
$151,201
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Berry, Ryan; Jeffery, Elise; Rodeheffer, Matthew S (2014) Weighing in on adipocyte precursors. Cell Metab 19:8-20
Jeffery, Elise; Berry, Ryan; Church, Christopher D et al. (2014) Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 3:206-11
Church, Christopher D; Berry, Ryan; Rodeheffer, Matthew S (2014) Isolation and study of adipocyte precursors. Methods Enzymol 537:31-46
Scheller, Erica L; Troiano, Nancy; Vanhoutan, Joshua N et al. (2014) Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. Methods Enzymol 537:123-39
Berry, Ryan; Church, Christopher D; Gericke, Martin T et al. (2014) Imaging of adipose tissue. Methods Enzymol 537:47-73
Berry, Ryan; Rodeheffer, Matthew S (2013) Characterization of the adipocyte cellular lineage in vivo. Nat Cell Biol 15:302-8
Birsoy, Kivanc; Berry, Ryan; Wang, Tim et al. (2011) Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis. Development 138:4709-19
Festa, Eric; Fretz, Jackie; Berry, Ryan et al. (2011) Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146:761-71